A crystalline complex of cephaloridine with an alkane diol

ABSTRACT

A crystalline solvate of cephaloridine with certain alkane diols, e.g., propane -1,3-diol, butane -1,3-diol and butane -2,3diol, a process for the preparation of such solvates and pharmaceutical compositions containing the solvates.

United States Patent m1 Chapman et al. 1 Jan. 2, 1973 [$4] CRYSTALLINECOMPLEX OF [58] Field of Search ..260/243 C CEPHALORIDINE WITH AN ALKANE[)IQL [56] References Cited [75] Inventors: John H. Chapman, Middlesex;UNITED STATES PATENTS Susan E. Stanil'orth, London, both o England3,352,859 11/1967 Higgins et al. ..260/243 C [73] Assignee: GlaxoLaboratories Limited, Mid- Primary RiZZO Cues, d Attorney-Bacon & Thomas[22] Filed: July 7, 1970 [57] ABSTRACT PP'- 53,020 A crystalline solvateof cephaloridine with certain alkane diols, e.g., propane -l,3-diol,butane -l,3-diol and butane -2,3-diol, a process for the preparation of[30] Foreign Apphauon Priority Data such solvates and phannaceuticalcompositions con- July 24, I967 GreatBritain...........,..,......37,298/69 mining the solvatesr 52 us. Cl...260/243 0, 424/246 Drama CRYSTALLINE COMPLEX OF CEPl-IALORIDINE WITHAN ALKANE DIOL This invention is concerned with crystalline solvates ofN-[7B-(Z-thienylacetamido)ceph-3-em-3-ylmethyl] pyridinium-4-carboxylate(common name cephaloridine) and with techniques for the preparation ofsuch solvates.

Several different crystalline forms of cephaloridine are known [seeChapman et al. J. Pharm. Pharmac., (I968), 20, 418-429]. The aand 3-forms have good solubility and rate of solution in water and hencepossess important advantages in use over other forms of cephaloridinesuch as the 8-form. The aand fl-forms of cephaloridine do not, however,possess good thermal stability.

It is desirable to have available crystalline forms of cephaloridinethat combine the advantages of the aand B-forms with good thermalstability. We have found that this is largely achieved by certaincrystalline solvates of cephaloridine. Furthermore these solvates arerelatively non-hygroscopic.

According to the invention therefore there is provided a crystallinesolvate of cephaloridine with an alkane diol having three to eightcarbon atoms, two or three of the carbon atoms linking the oxygen atomsof the hydroxy groups, e.g., an alkane diol of the formula:

H OH

wherein R and R, which may be the same or different, are each a hydrogenatom or a methyl group; and n is l or, when R R=CH n is l or 0.

Alkane diols of formula (1) include propanel ,3-diol, butane-1,3-diol,butane-2,3-diol, and pentane-2,4-diol.

The solvates appear to be 1:] stoichiometric complexes of cephaloridineand the chosen diol.

The solvates may be prepared by, for example, contacting an acidaddition salt of cephaloridine with the alkane diol in an aqueous ororganic medium containing or to which is added an inorganic or organicbase and allowing the solvate to crystallize out. The solvates may thusbe prepared by:

i. contacting an aqueous or an organic solution of the cephaloridinesalt containing the base with the diol;

ii. adding the base to a suspension or solution of the cephaloridinesalt in an organic or aqueous medium containing the diol; or

iii. adding the base and the diol to a suspension or solution of thecephaloridine salt in an organic or aqueous medium.

The solvate crystallizes from the solution and may be collected byfiltration and worked up in the usual manner.

Suitable organic media which may be used can be selected from thosedescribed in British Pat. No. l,ll ,561, e.g dimethylformamide ordimethylacetamide.

The organic base may be a tertiary organic base such as a tri-(loweralkyl)amine, e.g., triethylarnine. Preferably the organic base will havea pKb (as measured in water) of less than 6. Suitable inorganic basesinclude alkali metal and ammonium salts of weal: acids, e.g., thosehaving a pKa (as measured in water) greater than 4, e.g., carbonic acidand acetic acid, such as, for example, ammonium acetate and sodiumbicarbonate.

Suitable acid addition salts for use in the preparation of the solvatesinclude those deriving from acids having a pKa of 4 or less (as measuredin water), e.g., the hydronitrate, hydrochloride, hydrobromide,sulphate, or phosphate. We particularly prefer to employ cephaloridinehydronitrate since this can be prepared in a state of high purity.

An alternative method of preparing the solvates according to theinvention is by crystallization of the solvate from a solution orsuspension of cephaloridine containing the alkane diol. This may beeffected by dissolving cephaloridine in water, contacting the aqueoussolution with the diol and allowing the cephaloridine solvate tocrystallize out.

To complete crystallization it may be desirable to add a non-solvent,e.g., acetone to the mixture.

In cases where the chosen diol can exhibit optical activity it appearsthat only one optical isomer of the diol takes part in solvate formationwith the cephaloridine, the other form apparently remaining unreactive.For example, in the case of a racemic mixture of butanel,3-diol only thedextrorotary form takes part, the excess laevorotary form remaining insolution.

The solvates according to the invention may be formulated foradministration in any convenient way by analogy with other antibioticsubstances, such as penicillin and neomycin, and the invention thusincludes within its scope a pharmaceutical composition for use in humanor veterinary medicine comprising a crystalline solvate of cephaloridinewith the alkane diol in association with a pharmaceutical carrier orexcipient.

The solvents may thus be made up into injectable preparations insolution in suitable media, e.g., sterile, pyrogen-free water or as drypreparations suitable for the extempore preparation of injectablepreparations. The compositions may further take the form of preparationsfor topical use, e.g., lotion ointments or creams, formulated withsuitable excipients for such preparations.

For veterinary medicine the solvates may be form ulated in a mannerconventional in veterinary medicine particularly for injection asveterinary cerates with a veterinary create base.

In general the dosages employed in human medicine on adults will rangefrom 200 mg (calculated as cephaloridine) of the compound per doseupwards, administered for example four times a day.

The solvates according to the invention may be administered incombination with other antibacterial antibiotics especially thepenicillins such as penicillin G and/or the tetracyclines.

In order that the invention may be well understood the followingexamples are given by way of illustration only.

The test referred to in the examples is an accelerated color test inwhich a small sample of the material under investigation is heated for20 minutes in a test tube dipping into a boiling water bath. The degreeof thermal stability is then measured by examining a 2 cm. layer of a10% (w/v) aqueous solution of the material in a Lovibond tintometer. The100 test may be regarded as a qualitative assessment of the degree ofthermal stability by the test material. Low readings in this testindicate good thermal stability. The a-form of cephaloridine gives areading of about 4.0Y, 0.8R. (Y yellow; R red).

Preparation of cephaloridine butane-l,3-diol solvate form cephaloridinehydronitrate a. Cephaloridine hydronitrate (2 g) is suspended in water(5 ml) and triethylamine 1 ml) is added whereupon all of the soliddissolves. Butane-l,3-diol 10 ml) is added and a solvate slowlycrystallizes out. Excess acetone (50 ml) is added to completecrystallization. The solvate is filtered off, washed withacetone/butanel,3-diol/water then acetone, and dried at 35 under reducedpressure for 18 1 (Nujol) 1775 (B-lactam), 1672 and 1544 (CONH), 1612(CCO), 742, 720 and 682 cm (CH bending). A 240 nm E 316, A 255 nm E 293(ratio 1.08). The n.m.r. (D spectrum resembles that of the a-form ofcephaloridine with the addition of 1 mole of butane-1,3-diol at 6.01,6.28, 8.26 and 8.75 (Found: C, 54.3; H, 5.3; N, 7.9; S, 12.5;c,,l-|,,o,N,s, requires C, 54.6; H, 5.4; N, 8.3; S, 12.7%).

b. Cephaloridine hydronitrate (2g) is dissolved in butane-1,3-diolacetonitrile, 1:1 (30 ml). Triethylamine (1 ml) is added and a solvateslowly crystallizes out. Excess acetone (20 ml) is added to completecrystallizatlon.

c. Cephaloridine hydronitrate (3 g) is dissolved in dimethylacetamide (5ml). Triethylamine (1.5 ml) and butane-1,3-diol ml) are added and asolvate immediately crystallizes out. Excess acetone ml) is added tocomplete crystallization and ease filtration.

EXAMPLE 2 a. Preparation of cephaloridine butane-1,3-diol solvate formaor G-cephaloridine aor fi-cephaloridine (2 g) is dissolved with warmingin water (5 ml) and butane-1,3-diol (5 ml) is added. Aftercrystallization has occurred acetone (50 ml) is added to completecrystallization.

b. Preparation of cephaloridine butane-1,3-diol solvate from 8- oru-cephaloridine 8- or u-cephaloridine (2 g) is shaken for 6 hours withbutane-1,3-diol (20 ml). After filtering, washing with acetone andcrying, the solid is found to have become the butane-1,3-diol solvate.

EXAMPLE 3 Cephaloridine butane-1,3-diol solvate Cephaloridine (S-form9.76 g dry weight) was dissolved in water (20 ml) by warming to 35.Butane-l,3- diol (40 ml) was added. The solution was stirred slowly andseeded with a few crystals of cephaloridine butanel,3-diol solvate. Thetemperature was lowered to and crystallization commenced after 5 minutesstirring. Stirring at 25 was continued for 3 36 hours before coolingwith stirring to 6 during 1% hours.

The product was collected by vacuum filtration and washed bydisplacement with 10 percent aqueous butane-1,3-diol (20 ml) followed byacetone slurries (2 X 20 ml) and an acetone displacement wash (20ml).The white crystalline solid was dried for 18 hours at 40 in vacuo togive cephaloridine butane-1,3-diol solvate (11.17 g, 94.0% theory) [a],42.l (c 1.0 in water) Found: C 54.4; H 5.3; C H O,N,S,, C,H, O, requiresC 54.6; H 5.4%, n.m.r. (13,0) showed one mole of hutane-l ,3-diol permole of cephaloridine. 100 test 0.4Y, 0.011.

EXAMPLE 4 Cephaloridine butane-1,3-diol solvate Cephaloridine (8-form9.76g dry weight) was dissolved in water (25ml) at 35. The solution wascooled to 25 and a solution of butane-1,3-diol (50 ml) in acetone (200ml) was added over 1% hours. Seeding with the solvate was carried outafter the first 20 minutes. On completion of the addition, stirring wascontinued at 25 forafurther l /4 hours.

The product was collected by vacuum filtration and slurried with acetone(2 X 20 ml) followed by an acetone displacement wash (20 ml). The whitecrystalline solid was dried for 18 hours at 40 in vacuo to givecephaloridine butane-1,3-diol solvate (10.40g, 87.5% theory).[a],,+43.6; n.m.r.(D,O) as above. Found: C 54.5; H 5.3%. l00 test:0.7Y,0.2R.

EXAMPLE 5 Cephaloridine butane-1,3-diol solvate.

Cephaloridine hydronitrate (9.7 g) was suspended in water (25 ml) andtreated with triethylamine (3 ml) to give a clear yellow solution. Thesolution was stirred at 20 and a mixture of butane-1,3-diol (50 ml) andacetone (200 ml) was added rapidly. Crystallization began after about 10minutes and gentle stirring was continued for 4 hours. The solid wascollected by filtration, washed with butane-1,3-diol in acetone (10% 25ml), slurried with acetone (25 ml) and finally washed by displacementwith acetone (25 ml). The product was dried at 40 in vacuo overnight togive cephaloridine butane-1,3-diol solvate (9.5 g; 93.0% theory) [e143.6 n.m.r. (D,O) as above. Found: C 54.4;H 5.2%. 100 test:0.8Y,0.3R.

EXAMPLE 6 Cephaloridine butane-1,3-diolsolvate Cephaloridinehydronitrate (9.7 g) was dissolved in water (25 ml) containingtriethylamine (3slowly ml) at 20. The solution was filtered and thenadded alowly to a well-stirred, seeded mixture of butane-1,3-diol (50ml) and acetone (200 ml) at 20. Stirring was continued for 4 hours andthe solid was collected, washed and dried as above to give cephaloridinebutane-1,3- diol solvate (9.0 g; 88.1% of theory) [01],, 44.7 n.m.r.(D,O) as above. Found: C 54.9; H 5.4%. 100 test 0.5Y, 0. l R.

EXAMPLE 7 Cephaloridine butane-1,3-diol solvate Cephaloridinehydronitrate (10 g) was dissolved in water (15 ml) containingtriethylamine (3 ml) at 20. Butane-[,S-diol (50 ml) was added as asingle charge and the mixture was stirred for 4 hours at 20. The solidwas collected, washed and dried as above to give cephaloridinebutane-1,3-diol solvate (9.3g, 91.0% theory). [111 43.l; n.m.r. (D 0) asabove. Found: C 54.5; H 5.3%. 100 test 0.2Y, 0.1R.

EXAMPLE 8 Cephaloridine propane-1,3-diol solvate Cephaloridinehydronitrate (5 g) is suspended in propane-1,3-diol ml) andtriethylamine (2.5 ml) added whereupon all the solid dissolves. Asolvate then slowly crystallizes out and acetone (50 ml) is added tocomplete crystallization. The solvate is filtered off,

washed with acetone and dried at 35 under reduced pressure for 18 hours.1 (Nujol) 1782 (B-lactam), 1680 and 1562 (CONl-l), 1620 (COO'), 797,778, 746, 717 and 685 cm (CH bending). A 240 nm E 321, A 255 nm E 299(ratio 1.08) (calc. for 1 mole propane-1,3-diol 322, 293). The n.m.r.(D,O) spectrum resembled that of unsolvated cephaloridine, with theaddition of peaks at 8.20 and 6.30 'r corresponding to I molepropane-1,3-diol. (Found: C, 53.2; H, 5.2; N, 8.4; C, 13.2; C,- -H,-,O,N S, requires C, 53.8; H, 5.1;N, 8.5; S, 13.0%). 100 test 0.8Y,0.311.

EXAMPLE 9 Cephaloridine butane-2,3-diol solvate Cephaloridinehydronitrate (2 g) is dissolved in butane-2,3-diol:acetonitrile,l :1ml). Triethylamine (1 ml) is added. A solvate crystallizes out oncooling, and acetone (50 ml) is added to complete precipitation. u(Nujol) 1780 (B-lactam), 1675 and 1567 (CONH), 1615 (COO'), 777, 737,719 and 687 (CH bending). A 240 nm E 313, A 255 nm E,,,,,," 288 (ratio1.09) (Calc. for 1 mole butane-2,3-diol 313, 285). n.m.r. (D 0)additional peaks at 8.76, 6.31 for 1 mole butane-2,3-diol. (FoundzC,53.7; H 5.0; N, 8.0; S, 12.4 C H OW S, requires C, 54.6; H,5.4; N,8.3;S,12.7%).100test:0.5Y,0.3R.

EXAMPLE l0 Cephaloridine pentane-2,4-diol solvate Cephaloridine (1 g 8-form) is dissolved with warming in water (2 ml) and pentane-2,4-dio1 (10ml) is added. The solvate crystallizes out at room temperature, andacetone (25 ml) is added to complete precipitation. u (Nujol) 1780(B-lactam), 1682 and 1549 (CONH), 1615 (COO) 797,777, 735 and 689 cm (CHbending). A 240 nm E 304, A 255 E 278 (ratio 1.09) (calc. for 1 molepentane-2,4- diol', 305, 277). n.m.r. (D 0) additional peaks at 8.78,8.38 and 6.0 r for 1 mole pentane-2,4-diol. (Found C, 55.2; H, 5.3; N,7.7; S, 12.3 C, H O,N,S, requires C, 55.5; H,5.6; N, 8.1; S, 12.3%). 100test: 0.5Y, 0.1R.

EXAMPLE l1 Cephaloridine butane-1,3-diol solvate Cephaloridinehydronitrate (9.73 g) was added portionwise to a stirred suspension ofsodium bicarbonate (1.8 g) in water (12 ml). The solid dissolved slowlywith evolution of carbon dioxide. The clear solution was added dropwiseto stirred butane-1,3-dio1 (50 ml), and washed in water with (3 ml). Themixture was stirred at for 4 hours. The solid was collected byfiltration and washed with a 10 percent solution of butane-1,3-diol inacetone ml) and with acetone (2 X 25 m1) and dried overnight at 40 invacuo to give cephaloridine butane-1,3-dio1 solvatc (9.3g; 90.5% oftheory) n.m.r. (D O) showed one mole of butane-1,3-

-diol per mole of cephaloridine. Found: C 54.3%; H

5.3%. l00test: 0.1Y; 0.0K.

EXAMPLE 12 Cephaloridine butane-1,3-diol solvate Cephaloridinehydronitrate (9.73 g) was added portionwise to a solution of ammoniumacetate 1.6 g) in water 12 ml) to give a clear solution, which was addeddropwise over 20 minutes to stirred butane-1,3-diol (50 ml) containing afew seeds of the cephaloridine solvate and washed in with water (3 ml).The mixture was stirred at 20 for 4 hours. The solid was collected byfiltration, washed with a 10 percent solution of butanel,3-diol inacetone (25 ml) and with acetone (2 X 25 ml), and then dried overnightat 40 in vacuo to give cephaloridine butane-1,3-diol solvate (9.3g 90.5%of theory) n.m.r. (D,O) showed one mole of butane-1,3- diol per mole ofcephaloridine. Found: C 54.6%; H 5.4%. test 0.2Y, 0.0R.

EXAMPLE 13 Cephaloridine butane-1,3-diol solvate Cephaloridine (8-form,dry wt. 9.64 g.) was dissolved in water (25 ml.) at 35. The solution wasadded to butane-1,3-diol (50 ml.) at 25 with stirring. The mixture wasseeded and stirred at 25 for 3 hours. The temperature was lowered to 5during 1 hour and the mixture was kept in the refrigerator overnight.

The product was filtered and washed with 10 percent aqueousbutane-1,3-diol (20 m1.), followed by acetone slurries (2 X 10 ml.) andan acetone displacement wash (20 ml.)

The solid was dried for 18 hours in vacuo at 40 to give cephaloridinebutane-1,3-diol solvate (10.72 g. 91 .5% theory) [01] 42.5 (c 1.0 inwater). N.m.r. (D,O) showed one mole of butane-1,3-diol per mole ofcephaloridine. (Found: C 54.4; H 5.4; N 8.2%.) 100 test 0.4Y, 0.0R.

EXAMPLE l4 Cephaloridine butane-1,3-diol solvate Cephaloridinehydronitrate (9.73 g. dry wt.) was dissolved in a mixture of water 12m1.) and triethylamine (3 ml.) and the solution was added dropwise over10 minutes to stirred butane-1,3-diol at 20, containing a seed of thecephaloridine solvate. The aqueous solution was followed through by awater wash (3 ml.).

The mixture was stirred at 20 for 4 hours. The solid was collected andwashed by displacement with 10 percent aqueous butane-1,3-diol (10 ml.)and 10 percent butane-1,3-diol in acetone (25 ml.), followed by anacetone slurry (25 ml.) and a displacement was with acetone (25 ml.).The product was dried at 40 in vacuo to give cephaloridinebutane-1,3-diol solvate (9.3 g.; 90.5% theory) [al 44.6; n.m.r. (D 0)showed one mole of butane-1,3-diol per mole of cephaloridine. (Found: C,54.7; H, 5.4; N, 8.0%). 100 test 0.3Y, 0.0R.

X-ray crystallographic data in respect of the five cephaloridinesolvates prepared in the Examples are given in the following tables.lnterplanar spacings [d (A)] as measured from using copper Kat-radiationare given as well as relative intensities of the lines according to thefollowing arbitrary basis:

s strong m medium w weak f faint v very d diffuse 9 l 3. A crystallinecomplex as defined in claim 1 the alkane diol in a medium to which isadded an inorwherein said alkane diol is propane-l ,3'diol. ganic baseor an organic base having a pKb of less than 4. A crystalline complex asdefine n C a m 1 6 and allowing the solvate to crystallize out. whereinsaid alkane diol is butane-1,3-diol. 3 A process as d fin d in claim 7 hi said 5. A crystalline complex as defined in claim 1 5 wherein saidalkane diol is butane-2,3-diol.

6. A crystalline complex as defined in claim I wherein said alkane diolis pentane-2,4-diol. weak acid 7. A process for the preparation of acrystalline l:l A d f l 7 h stoichiometric complex of cephaloridine asdefined in 10 pmc,ess as e "i? m 0 am w erem Sal claim 1 which comprisescontacting an addition salt of addmon salt cephalondme hydromtrate'cephaloridine and an acid having a pKa of4 or less with ganic base is atri-(lower alkyl)amine.

9. A process as defined in claim 7 wherein said inorganic base is analkali metal or ammonium salt of a

2. A crystalline complex as defined in claim 1 wherein said alkane diolhas the formula: wherein R1 and R2 are independently selected from thegroup consisting of hydrogen and methyl and n is selected from the groupconsisting of 1 and, when R1 and R2 are both methyl, 0 and
 3. Acrystalline complex as defined in claim 1 wherein said alkane diol ispropane-1,3-diol.
 4. A crystalline complex as defined in claim 1 whereinsaid alkane diol is butane-1,3-diol.
 5. A crystalline complex as definedin claim 1 wherein said alkane diol is butane-2,3-diol.
 6. A crystallinecomplex as defined in claim 1 wherein said alkane diol ispentane-2,4-diol.
 7. A process for the preparation of a crystalline 1:1stoichiometric complex of cephaloridine as defined in claim 1 whichcomprises contacting an addition salt of cephaloridine and an acidhaving a pKa of 4 or less with the alkane diol in a medium to which isadded an inorganic base or an organic base having a pKb of less than 6and allowing the solvate to crystallize out.
 8. A process as defined inclaim 7 wherein said organic base is a tri-(lower alkyl)amine.
 9. Aprocess as defined in claim 7 wherein said inorganic base is an alkalimetal or ammonium salt of a weak acid.
 10. A process as defined in claim7 wherein said acid addition salt is cephaloridine hydronitrate.